Cannabis use and mood disorders: a systematic review

Background Problematic cannabis use is highly prevalent among people with mood disorders. This underscores the need to understand the effects of cannabis and cannabinoids in this population, especially considering legalization of recreational cannabis use. Objectives We aimed to (1) systematically evaluate cross-sectional and longitudinal studies investigating the interplay between cannabis use, cannabis use disorder (CUD), and the occurrence of mood disorders and symptoms, with a focus on major depressive disorder (MDD) and bipolar disorder (BD) and; (2) examine the effects of cannabis on the prognosis and treatment outcomes of MDD and BD. Methods Following PRISMA guidelines, we conducted an extensive search for English-language studies investigating the potential impact of cannabis on the development and prognosis of mood disorders published from inception through November 2023, using EMBASE, PsycINFO, PubMed, and MEDLINE databases. Results Our literature search identified 3,262 studies, with 78 meeting inclusion criteria. We found that cannabis use is associated with increased depressive and manic symptoms in the general population in addition to an elevated likelihood of developing MDD and BD. Furthermore, we observed that cannabis use is linked to an unfavorable prognosis in both MDD or BD. Discussion Our findings suggest that cannabis use may negatively influence the development, course, and prognosis of MDD and BD. Future well-designed studies, considering type, amount, and frequency of cannabis use while addressing confounding factors, are imperative for a comprehensive understanding of this relationship. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023481634.


Introduction
Mood disorders represent a substantial global mental health challenge, with major depressive disorder (MDD) affecting up to 15% of the population, or approximately 300 million individuals worldwide (1).Moreover, bipolar disorder (BD) exhibits a lifetime prevalence of 1.9%, with an additional 4.6% of individuals experiencing subclinical presentations (e.g., cyclothymia) (2).These disorders typically start in adolescence and follow a chronic course, commonly leading to substantial functional impairment (3,4).Moreover, both MDD and BD contribute significantly to years marked by disability, underscoring their profound impact on quality of life and well-being.

Inclusion and exclusion criteria
We considered observational studies focusing on the influence of cannabis on the initiation of mood disorders, giving priority to both longitudinal and cross-sectional studies.Included studies were required to assess major depressive disorder (MDD), bipolar disorder (BD), mania, hypomania, suicidality, dysthymia, or depressive symptoms using validated clinical tools.For studies investigating the development of mood disorders or symptoms, we additionally limited our scope to studies conducted in the general population.In the context of studies evaluating the effects of cannabinoids on the treatment outcomes and prognosis of MDD and BD, we considered both experimental and observational studies.Despite the anticipated limited availability of large, well-controlled randomized controlled trials (RCTs) in this domain, our search maintained inclusivity to comprehensively assess the available literature.
We excluded the following from our review: (a) literature reviews, meta-analyses, dissertations, commentaries, conference presentations, abstracts, and case studies; (b) studies examining the effect of mood disorders on subsequent cannabis use; (c) studies lacking a baseline measure of cannabis use; (d) animal models of cannabis use; (e) studies involving a special population (e.g., persons living with human immunodeficiency virus) and; (f) non-English publications.

Data extraction and quality assessment
Data was extracted by one reviewer (MS).The following variables from each article were recorded: author, publication year, study design, number of participants, age range of participants, follow-up time, cannabis use measure, mood disorder/symptom measure, and relevant findings.
The Newcastle-Ottawa Scale (NOS) evaluated the quality of included observational studies (23).The NOS assesses non-randomized studies on a scale from 0-9 based on three main criteria: (1) selection of cases and controls (e.g., adequate definition, representativeness, and selection of cases); (2) comparability of cases and controls (e.g., adequate controlling or adjustment for confounding variables); and (3) ascertainment of exposure (e.g., adequate assurance that the cases were exposed to the variable of interest).Studies receiving a score ≥ 7 on the NOS are categorized as high quality, while studies receiving a score ≤ 4 are considered to exhibit low methodological quality (23).We evaluated the quality of randomized controlled trials (RCTs) by assessing their risk of bias, through the Cochrane Collaboration Risk of Bias tool 2.0 (RoB) (24).For non-randomized interventions, the ROBINS-I tool was implemented (25).Each study was categorized as having high, low, or unclear risk in domains such as randomization, intervention adherence (deviation from intended interventions), missing outcome data, outcome measurement, and selective reporting.The worst grading on individual items defines the overall risk of bias for each single study.

Study characteristics
Our initial literature search yielded a total of 3,262 studies.After eliminating 167 duplicates, we retained 3,095 records for screening based on their titles and abstracts.Following this screening process, 118 articles underwent full-text review.Of these, 78 papers met our inclusion criteria.Specific reasons for exclusion are listed in the PRISMA flowchart (Figure 1).The included studies spanned from 2001 to 2023 and were conducted in a wide range of countries.Among the 78 studies, there was one RCT, specifically examining the therapeutic potential of cannabidiol in treating BD (26).The remaining were observational or non-randomized in nature, with 52 adopting longitudinal designs and 25 utilizing cross-sectional designs.All but three publications (26-28) relied on self-report measures to assess cannabis use.Forty-eight studies examined the connection between cannabis use and MDD or depressive symptoms, 27 studies examined the relationship between cannabis use and BD or mania, and 3 studies examined the relationship between cannabis use and both depressive and manic symptoms.Table 1A outlines crosssectional and longitudinal studies examining the association between cannabis use and MDD symptoms and diagnoses, while Table 1B addresses the corresponding relationship with manic symptoms and BD diagnoses.Table 2A provides a detailed account of cross-sectional and longitudinal studies that explore the impact of cannabis use on MDD while Table 2B examines the corresponding relationship within BD.
The complete risk of bias assessment for each study is reported in Tables 3, 4. Concerning the NOS ratings, 78.7% (59 out of 75) of the studies exhibited high methodological quality, with the remaining

Relationship between cannabis use, depressive symptoms and MDD diagnoses
Nine studies examined the cross-sectional relationship between cannabis use and depressive symptoms or MDD diagnoses, with seven identifying significant associations (30, 46-48, 69, 86, 101).In a retrospective analysis of data from the Australian Twin Registry, frequent cannabis use (≥ 100 times across their lifetime) was associated with MDD and suicidal ideation in both monozygotic and dizygotic twins (30).In a similar study using nationally representative data to investigate the relationship between cannabis use and a pastyear experience of a major depressive episode (MDE), Fairman et al. (48) found that, compared to individuals with no cannabis use, those reporting both early-onset and adult-onset cannabis use had an increased likelihood of experiencing a MDE, even after adjusting for other substance use (with odds ratios of 1.7 and 1.8, respectively).These findings contrast with an epidemiological study conducted in the UK among young adults, where self-reported use of high-or low-potency cannabis did not correlate with a diagnosis of MDD after controlling for relevant factors, including other substance use (61).Similarly, Chabrol et al. found no significant association between cannabis use disorder (CUD) with suicidal ideation or depressive symptoms in a sample of 1,034 French postsecondary students (38).
In two smaller cross-sectional studies that examined the role of cannabis use in depressive symptoms among youth, cannabis use emerged as a significant predictor of this outcome (47,101).Medina and colleagues (101) demonstrated that adolescent cannabis users, in comparison to never users, had exhibited neural abnormalities, including reduced hippocampal volumes and white matter alterations, along with higher levels of depressive symptoms.In a separate study examining depressive symptoms among 707 Spanish youth, Espada and colleagues (47) found that, after controlling for alcohol and tobacco use, adolescents who reported past 30-day cannabis use reported significantly higher levels of depressive symptoms than non-users.
Thirty-one studies prospectively explored the relationship between cannabis use and subsequent depression, including depressive symptoms, MDD diagnoses, and suicidality.Among these studies, 22 identified a significant temporal association between baseline cannabis use and subsequent depression.Cannabis use was a significant predictor of adulthood depression across 12 sample sets following adolescents (20,34,42,59,60,66,70,74,78,82,84,89).In a sample of LGB and heterosexual adolescents, London-Nadeau and colleagues observed that cannabis use at age 13 predicted depression symptoms at ages 15 and 17 among LGB participants only (70).However, a bidirectional relationship was also identified among LGB adolescents, where baseline depressive scores predicted subsequent cannabis use.In one study that tracked a cohort of Australian young adults from birth, and after controlling for covariates, individuals who used cannabis at least once a week were more likely to report depressive symptoms than those who never used cannabis or those who used       In prospective studies that identified gender-specific effects between cannabis use and subsequent depression, findings were mixed.In a nationally representative study of American youth and adults by Carra and colleagues (37), it was found that women who reported cannabis use at baseline were more likely than men to experience a major depressive episode (MDE) 1 year later.Moreover,  (84).In contrast, three studies detected stronger associations between cannabis use and subsequent depressive symptoms in men (39,50,66,90).A longitudinal study spanning 4 years and involving 951 adolescents observed that increases in cannabis use were associated with increases in the severity of depressive symptoms in boys only (50).Three prospective studies examined the link between cannabis use and suicidality, with all reporting significant associations (55,85,90).In a study that followed adolescents for 13 years, the authors found that while frequent or any cannabis use did not predict later depression, any cannabis use was linked to later suicidal ideation, and frequent use was associated with suicide attempts (85).
However, nine longitudinal studies did not establish a temporal relationship between cannabis use and subsequent depressive symptoms or diagnoses when controlling for relevant confounding variables, including other alcohol or substance use (35,41,49,56,58,71,87,99,103).In a recent study examining the relationship between various substance use disorders (SUDs) and the incidence of a first MDE, Hassan et al. (58) found that CUD alone did not increase the likelihood of experiencing a MDE 1 year later.However, the comorbidity of CUD and opioid use disorder (OUD) significantly increased this association.Moreover, two prospective studies found that while baseline cannabis use did not predict a diagnosis of MDD at follow-up, baseline severity of depressive symptoms was predictive of subsequent cannabis use (49,87).

Relationship between cannabis use, mania, and BD diagnoses
Five studies examined the cross-sectional association between cannabis use and the presence of (hypo) manic symptoms or the diagnosis of BD, all of which identified a significant relationship (29, 43,63,64,72).Lagerberg and colleagues (64) found a significant dosedependent relationship between cannabis use and age of onset for BD.This effect of cannabis was not confounded by multiple variables, including gender, family history of BD, lifetime psychotic symptoms, and other substance or alcohol use.Similarly, in a retrospective chart review of more than one million Australian patients, which focused on the relationship between SUDs and mental health disorders, Lai and colleagues found a significant association between CUD and BD diagnoses (72).
Moreover, seven studies prospectively examined the relationship between cannabis use and BD diagnoses and symptoms, with four establishing a significant association (21,44,76,95).In a nationally representative sample of Dutch adults, cannabis use at baseline nearly tripled the risk of reporting manic symptoms at a 3-year follow-up, even after controlling for confounds (21).No evidence of reverse causality was found.Similarly, Marwaha et al. (76) found that among 3,370 UK adolescents, cannabis use at least 2-3 times per week at baseline doubled the risk of reporting manic symptoms at a 6-year follow-up.
However, three studies did not detect a temporal relationship between cannabis use and BD diagnoses or symptoms (45, 49, 71).Using Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), Feingold et al. (49) found that baseline cannabis use was not associated with an increased incidence of BD or MDD when controlling for other substance use.In a separate epidemiological study that examined lifetime cannabis exposure and its association with BD within a Finnish birth cohort, no association was found between adolescent cannabis use and BD diagnosis in adulthood after adjusting for alcohol use, smoking, and lifetime drug use (45).

Impact of cannabis on the course of MDD
Five cross-sectional studies evaluated the effects of cannabis use in patients with MDD (40, 51, 79, 81, 88), with three identifying neural abnormalities compared to controls (40,51,79).Ford et al. (51) employed a passive music listening paradigm to investigate variations in reward processing in brain activity across four groups of youth: healthy controls, frequent cannabis users, individuals with MDD, and individuals with MDD who use cannabis.They observed significant hyperactivation in prefrontal and limbic regions during the task only within the MDD cannabis-using group.In a study assessing cognition and psychosocial functioning, Secora and colleagues found that adults with comorbid CUD and MDD reported more psychosocial impairments than those with CUD alone (88).However, when assessing memory, verbal skills, and attention, there were no significant differences between the two groups.Similar findings were noted in a more recent study that examined cognitive functioning and neural activity across four groups of adolescents: healthy controls, youth with current MDD without frequent cannabis use, youth with frequent cannabis use, and youth with frequent cannabis use and MDD (81).The authors found no evidence of cognitive impairments in any of the cannabis-using groups when compared to non-users.Furthermore, there was no interaction observed between MDD and cannabis use on resting state fMRI connectivity.When considering the longitudinal effects in MDD, six prospective studies demonstrated an adverse effect of cannabis use (19,27,28,32,33,36).In a recent open-label, single-arm investigation utilizing monetary contingency management (CM), the cognitive and clinical effects of 28 days of cannabis abstinence were examined in people with co-occurring MDD and CUD (27,28).With 8/11 participants achieving cannabis abstinence as confirmed by urine toxicology, significant improvements were observed in depressive symptoms and anhedonia (27), and in specific cognitive areas including visual search speed, visual sustained attention, response inhibition, and visuospatial working memory (28).Moreover, in a secondary analysis of a randomized controlled trial involving 307 outpatients with MDD receiving substance/alcohol use treatment, patients using cannabis for medical purposes experienced worse mental and physical health functioning at study endpoint, in comparison to non-users (32, 33).Furthermore, non-medical use of cannabis was linked to higher suicidal ideation, poorer global functioning, and fewer psychiatry visits.Over time, patients using non-medical cannabis exhibited less improvement in depression symptoms and suicidal ideation compared to non-users.Utilizing data from Waves 1 and 2 of NESARC, Feingold et al. ( 19) explored the effect of cannabis use and CUD on the course and outcome of MDD over a three-year period.Cannabis use at baseline was associated with a significant increase in depressive symptoms at follow-up, but did not correlate with suicidality, quality of life, or psychosocial functioning.Similar findings were obtained by Bovasso (36) where baseline CUD was predictive of worsened depressive symptoms, suicidal ideation, and anhedonia in a community sample of adults with MDD over a 2-year period.

Impact of cannabis on the course of BD
Of 13 cross-sectional studies that investigated cannabis use in BD, 11 identified a negative impact associated with this substance (29, 57, 62,64,67,68,80,83,92,93,97).In one study examining clinical characteristics associated with comorbid CUDs in BD inpatients, Weinstock et al. (97) found that CUD comorbidity was significantly associated with a greater presence of psychotic features, diagnosis at a younger age and a greater likelihood of meeting diagnostic criteria for an alcohol use disorder (AUD) or other SUD.Other evidence indicates that cannabis use in BD is associated with greater severity of depressive and manic symptoms (29,62,64,68), an increased number of hospitalizations (64,83), reduced medication adherence (80), greater disability (29) and a higher number of suicide attempts (29, 62).Moreover, two studies found that compared to BD-only patients, those with comorbid CUD exhibited a reduction in cortical thickness in frontal brain regions (57, 93).Similarly, Sultan and colleagues (92) observed that patients with BD and comorbid CUD demonstrated reduced resting-state functional connectivity across multiple frontaltemporal regions, in contrast to those with BD only.
However, two studies did not find a significant relationship between cannabis use and BD-related outcomes (75, 94).In a retrospective chart review, Maremmani and colleagues discovered that, contrary to their initial hypothesis, hospital discharge rates were comparable between BD patients with CUD and BD patients without cannabis use (75).In a separate study that compared various cognitive outcomes among three distinct groups, including adolescents with BD and no history of cannabis use, those with BD and cannabis use, and healthy controls without cannabis use, the authors found that the BD and cannabis use group and the BD group exhibited similar cognitive performance, which was inferior to controls (94).This finding contradicted the researchers' initial hypothesis that cannabis use exacerbates cognitive impairments in adolescents with BD.
Five of the studies included in the review prospectively explored the effects of cannabis in BD.All of these studies (31,91,96,100), except one (104), revealed negative outcomes linked to cannabis use.In a 2-year prospective observational study, individuals with BD who continued using cannabis demonstrated lower recovery rates and remission, in addition to poorer psychosocial functioning than never users and those who reduced their cannabis use (100).In a study examining clinical outcomes among a sample of 3,459 European patients diagnosed with BD, those who self-reported cannabis use exhibited reduced treatment compliance, increased illness severity, and lower satisfaction with their quality of life at a one-year follow-up (96).Other evidence suggests that cannabis use in BD is temporally associated with severity of mania (31), greater number of manic and depressive episodes (91), and rapid cycling (91).
However, in a prospective observational study that examined the immediate effects of smoking cannabis on mood in BD, results showed that the BD group experienced significant mood improvement compared to the group who used cannabis without BD (54).This improvement was evident in reductions in total mood disturbance as measured by the Profile of Mood States.These findings provide empirical support for anecdotal reports indicating that cannabis is sometimes used to alleviate mood-related symptoms (e.g., alleviation of cannabis withdrawal) in at least a subset of people with BD.
In the only randomized controlled trial (RCT) included in our review, Pinto and colleagues (26) investigated the potential of adjunctive cannabidiol (CBD; 0, 150 and 300 mg/day) for BD treatment.BD.Both the CBD and placebo groups exhibited a significant reduction in BD symptoms at study endpoint (Week 8), with no significant between group differences.Adverse events were comparable between groups, indicating that CBD could be a safe and well-tolerated treatment option.

Discussion
This systematic review provides a comprehensive assessment of the impact of cannabis use on the development of mood disorders and associated symptoms, specifically emphasizing MDD and BD.Furthermore, we examined how cannabis use impacts prognosis and treatment outcomes in people with MDD or BD.Our findings suggest that cannabis use is associated with elevated depressive and manic symptoms in the general population, as well as an increased risk of developing MDD and BD.Furthermore, there is minimal evidence to support the notion that cannabis improves clinical or treatment outcomes for MDD or BD; instead, its use is associated with a poorer prognosis for both disorders (see Table 5).
Our review serves as an extension of prior reviews and metaanalyses by identifying the associations between cannabis use and depressive and manic symptoms across both clinical and non-clinical populations.While previous reviews have focused particularly on specified clinical populations (105), or solely examined the prospective risk associated with cannabis use and mood disorders (106), our review uniquely bridges these perspectives.Furthermore, our review conducts a thorough investigation into the multifaceted impact of cannabis on a range of outcomes within MDD and BD.This exploration extends beyond the traditional focus on mood symptoms, encompassing critical domains such as cognition and neural functioning.We also examine the potential therapeutic effects of cannabinoids in mood disorders, noting that only one trial met the specified criteria (26).Overall, this expanded analysis enriches our comprehension of the intricate relationship between cannabis use and mood-related outcomes, offering a more holistic and comprehensive perspective.

Cannabis use, mood symptoms, and mood disorder diagnoses
We found that cannabis use is associated with elevated depressive symptoms, mania, and suicidality.Consistent with other reviews and meta-analyses (107-109), a dose-dependent relationship has been observed between the duration of cannabis use, particularly when initiated in adolescence, and the heightened occurrence of symptoms related to depression and mania [e.g., (37, 64)].These findings underscore the critical role of age of onset in cannabis use.Adolescence is a period of dynamic brain development, marked by significant structural and functional changes, including maturation of key brain regions implicated in mood regulation and emotional processing (110,111).This period represents a heightened vulnerability to the potential long-term consequences of environmental stressors, including THC exposure.Indeed, a recent review of over 30 human magnetic resonance imaging studies comparing former cannabis users with control groups has highlighted the emergence of neuroanatomical abnormalities among cannabis users in regions with a high density of CB1 receptors (112).
However, our review obtained some evidence that the relationship between cannabis and mood disorders may be influenced by additional factors, such as concurrent substance use (41, 45, 49).People who engage in cannabis use often co-use other substances (113,114).Importantly, these co-occurring substances also have the potential to impact brain development and influence mood.This underscores the critical need to account for other substance use when investigating the complex relationship between cannabis use and mood disorders.

Cannabis and the course of mood disorders
In MDD, we found compelling evidence indicating that cannabis use and CUD are linked to more pronounced symptomatology and a less favorable prognosis compared to patients who do not use cannabis.This includes greater levels of anhedonia (27,36), suicidality (33), reduced adherence (33) and poorer cognition (28).Notably, a study assessing the effects of 28 days of cannabis abstinence demonstrated substantial enhancements in specific cognitive domains and depressive symptoms (27,28).These findings imply that the adverse effects of cannabis use may be reversible.Nonetheless, it is imperative to acknowledge a significant limitation in this study-the absence of a non-abstinent control group.This limitation underscores the need for further controlled, long-term research to elucidate the impact of cannabis on clinical outcomes and cognition in MDD.Interestingly, other data suggests that cannabis use in MDD have better cognitive functioning than those who use cannabis without MDD (88).These findings underscore the need for more controlled research on cannabis and cognition in MDD.
Our systematic review also revealed a multitude of adverse consequences of cannabis use in people with BD.This includes more severe symptom profiles (29, 31, 96), a greater number of manic and depressive episodes (62,64), more rapid cycling (91) and higher levels of suicidality (29).Intriguingly, one study suggested that people with BD who use cannabis experienced greater immediate mood  (115,116), despite adverse longterm consequences.Moreover, we found evidence that baseline manic or depressive symptoms were predictive of subsequent cannabis initiation [e.g., (37, 50)].These findings have significant implications for treatment, suggesting that following the onset of a mood disorder, people may be more prone to initiate cannabis use.Given the available evidence indicating that cannabis use may be detrimental to people with MDD and BD, this association warrants further study.Thus, it is crucial for clinicians and researchers to explore alternative, evidence-based therapeutic approaches for people with mood disorders who may use cannabis for symptom management.
We found no compelling evidence supporting the therapeutic potential of cannabinoids in mood disorders.The only RCT included in our review that examined CBD's efficacy and safety for BD yielded inconclusive clinical results.Nonetheless, the findings indicate CBD's potential as a safe option, and further extensive clinical trials are warranted.Other research has evaluated cannabinoids such as dronabinol, nabilone, and nabiximols on depressive symptoms (117,118).These studies have been conducted within the context of treatment studies focused on other primary conditions, notably, chronic pain disorders.While there is some evidence that cannabinoids may offer benefits for mood and anxiety symptoms in specific patient populations (119), it is important to note that these people may not necessarily meet the clinical criteria for mood disorders.Overall, there is a need for further investigation, particularly in clinical cohorts with established mental health diagnoses.

Strengths and limitations
This systematic review has several notable strengths.First, the review encompassed a comprehensive range of studies, including both cross-sectional and prospective designs.This ensured a thorough examination of relationships between cannabis use and mood disorders, providing a holistic view of available evidence.Furthermore, we investigated a diverse set of outcomes.By considering various dimensions, such as depressive and manic symptoms, diagnostic outcomes, cognition, neuroimaging and treatment outcomes, this review provides multifaceted assessment of the impact of cannabis use on mood disorders.
However, there were several limitations.The inherent heterogeneity across the included studies, including variations in methodology, outcome measures, and participant characteristics is a significant limitation.For example, measurements of cannabis use exhibited substantial variability across studies, with many relying on single-item self-reports and few employing objective measures.This lack of standardized assessments of cannabis use introduces variability that may impact our findings.Future research would benefit from more comprehensive methods for quantifying cannabis use (e.g., urine toxicology).Second, few studies examined variables associated with cannabis use, including potency and route of administration, in relation to our outcomes.Two studies (36, 50) examined the relationship between low and high potency cannabis use and depressive symptoms and diagnoses, yielding mixed findings.In contrast, only one study (68) delved into the association between cannabis potency and the initial onset of a bipolar disorder episode, revealing a positive relationship.Relatedly, while only one of the included studies captured data on the route of cannabis administration, no analyses were reported on its relationship with mood symptoms (98).The route of cannabis administration may influence moodrelated symptoms through its impact on the speed of onset, bioavailability, peak concentrations, metabolism, and the context of use (120-122).Thus, studying these factors may be crucial for developing a nuanced understanding of how cannabis use may affect mental health.Furthermore, the review predominantly relies on observational studies, which inherently limited our ability to establish causality or determine the direction of the relationship between cannabis use and mood disorders.Moreover, several studies did not control for important confounding factors such as other substance misuse or psychosocial variables.Finally, the majority of included studies did not conduct gender-specific analyses, despite existing evidence indicating gender differences in the effects of cannabis use in the general population (123,124).This adds to the heterogeneity across studies and calls for more gender-inclusive research to better understand the nuances of this relationship.

Conclusion
We found that cannabis use is linked to increased depressive and manic symptoms in the general population, and an elevated risk of developing MDD and BD.Moreover, there was evidence of cannabisrelated harms in mood disorders.While these findings should be interpreted with caution when considering the observational nature of most eligible studies, the potential implications of these findings are substantial for practitioners and policymakers.Mental health practitioners should incorporate cannabis use screening into their standard assessments, ensuring that people with mood disorders are aware of the potential risks associated with cannabis use.Patients with mood disorders may use cannabis to manage mood symptoms, and clinicians should consider evidence-based alternatives for symptom management.Policymakers and public health officials may consider the need for targeted interventions and education programs focusing on the risks of cannabis use, particularly among people at risk for, or diagnosed with mood disorders.
Finally, a deeper exploration of the neurobiological underpinnings and causal relationships between cannabis use and mood disorders, both in human studies and animal models, would provide a more comprehensive understanding of the mechanisms involved.Moreover, well-controlled prospective studies with comprehensive assessments of cannabis use are needed to further elucidate the nuances of this relationship, while also considering sex-and gender-specific analyses.These studies will advance our knowledge and ultimately improve the mental health and well-being of people impacted by mood disorders.

Data availability statement
The data analyzed in this study is subject to the following licenses/ restrictions: the data that support the findings of this study are available on request from the corresponding author.Requests to access these datasets should be directed to tony.george@camh.ca.

FIGURE 1 PRISMA
FIGURE 1PRISMA flowchart of included studies.
TABLE 1A Summary of observational studies exploring the relationship between cannabis use, depressive symptoms, and MDD diagnoses (40 Studies, N = 1,015,726).

TABLE 1A (
(27,inued) methodological quality (21.3%; comprising 16 out of 75 studies).The ROBINS-I tool was applied to two studies conducted by the same research group(27, 28), where both studies displayed a high risk of bias.The only randomized controlled trial included in the review demonstrated a low risk of bias.

TABLE 1A (
Continued) TABLE 1B Summary of observational studies exploring the relationship between Cannabis use, manic symptoms, and BD diagnoses (12 Studies, N = 1,907,623).
TABLE 2A Summary of studies exploring the impact of cannabis on course of illness in MDD (11 Studies, N = 4,778).

TABLE 2A (
Continued) TABLE 2B Summary of studies exploring the impact of cannabis on course of illness in BD (19 Studies, N = 658,278).
SUDs, earlier age of onset of first manic and depressive episode, and a greater number of depressive, manic, or hypomanic episodes.

TABLE 3 Newcastle
Ottawa Scale (NOS) ratings for observational studies.
(82)tionship between cannabis use, depressive symptoms, and the serotonin transporter gene (5-HTTLPR) in adolescents(82).The serotonin transporter gene is highly regarded as a key candidate gene due to its involvement in development of depression and other mental health disorders [see (102)].Specifically, this gene encodes the serotonin transporter protein, which plays a crucial role in reuptake

TABLE 4
Risk of bias using Cochrane's risk of bias in non-randomized studies of interventions tool (ROBINS-I) and Cochrane's risk of bias tool (RoB-2).

TABLE 5
Overall trends in cannabis use and mood disorders.